Liposomes are widely used as models of biomembranes. Furthermore, they have recently been energetically investigated as a typical example of the drug delivery system (DDS).
However, when a water-soluble drug is encapsulated in liposomes by the conventional method, the encapsulation efficiency of drugs is generally low (in most cases 0.1 to 20%). There are two reasons: i) the mode of encapsulation of a low molecular weight water-soluble drug in liposomes basically consists distribution of the drug in the same concentration between the inner aqueous phase and outer aqueous phase of the liposomes and ii) for making liposomes stable as separate particles in an aqueous medium, it is necessarily required that the aqueous medium be present externally to liposomes as a dispersion medium therefor.
In view of the above, it has been considered very difficult to raise the drug encapsulation efficiency, in particular to a level close to 100%, when a water-soluble drug is caused to be encapsulated in liposomes.
Known methods for increasing the encapsulation efficiency of such a water-soluble drug or a drug having a small affinity for membranes include, among others, a) a reversed phase evaporation method (Proceedings of National Academy Sciences of U.S.A., 75, 4194, 1978), b) a chemical modification of drugs themselves (International Journal of Pharmaceutics, 14, 191, 1983; Journal of Pharmacobiodynamics, 7, 120, 1984; Chemical and Pharmaceutical Bulletin, 36, 3574, 1988), c) a use of other auxiliaries or the like (Journal of Pharmaceutical Sciences, 71, 958, 1982; Drug Development and Industrial Pharmacy, 10, 613, 1984), d) a modification of the properties of liposomal membranes themselves (Biochimica et Biophysica Acta, 812, 66, 1985; Biochimica et Biophysica Acta, 857, 123, 1986), and e) a use of a phospholipid having a charge opposite to the charge of the drug (Biochemical and Biophysical Research Communications, 107, 136, 1982; International Journal of Pharmaceutics, 17, 135, 1983; U.S. Pat. No. 4,769,250.
The prior art methods such as mentioned above are not satisfactory when a cation moiety-containing water-soluble drug is to be efficiently encapsulated in liposomes. In addition, when viewed as products for medical use, the liposomal products given by the prior art methods are quite unsatisfactory from the viewpoint of stability in blood.